Glucose, one of the most important energy sources for body, is taken up into a cell across cell membrane to be made available in the body. A membrane protein called glucose transporter is involved in this uptake at cell membrane. Glucose transporter is classified into two main categories of facilitated glucose transporter which uptakes glucose depending on intracellular and extracellular glucose concentration difference, and sodium/glucose cotransporter (SGLT) which uptakes glucose by using intracellular and extracellular ion concentration difference (for example, see Reference 1). Regarding SGLT, it has been known that SGLT1, sodium/glucose cotransporter having a high affinity, mainly exists in human small intestine, and SGLT2, sodium/glucose cotransporter having a low affinity, mainly exists in human renal tubule (for example, see References 2 and 3). It is reported that absorption of glucose and galactose is inadequate in patients with human SGLT1 dysfunction due to congenital abnormality, and that confirms SGLT1 participates in the absorption of glucose and galactose (see References 4 and 5). In addition, it has been confirmed that mRNA and protein of SGLT1 increase and the absorption of glucose or the like is accelerated in OLETF rat or streptozotocin-induced diabetic rats (for example, see References 6 and 7). In diabetic patients digestion and absorption of carbohydrates is generally accelerated, and it has been confirmed that, for example, hyperexpression of mRNA and protein of SGLT1 is found in human small intestine (for example, see Reference 8).
It is reported that SGLT2 is present in the segment S1 of renal proximal tubule and participates mainly in reabsorption of glucose filtrated through glomerulus (for example, see Reference 9).
Diabetes is one of lifestyle-related diseases with the background of change of eating habit and lack of exercise. Hence, diet and exercise therapies are performed in patients with diabetes. Furthermore, when its sufficient control and continuous performance are difficult, drug treatment is simultaneously performed. Now, based on the background of rapid increase of diabetic patients, various agents have been developed, and biguanides, sulfonylureas, insulin sensitivity enhancers, α-glucosidase inhibitors and the like have been employed. However, biguanides and sulfonylureas show occasionally adverse effects such as lactic acidosis and hypoglycemia, respectively. Insulin sensitivity enhancers show occasionally adverse effects such as edema, and are concerned for advancing obesity. In addition, α-glucosidase inhibitors that delay digestion and absorption of carbohydrates at the small intestine are used for improvement of postprandial hyperglycemia. It is reported that acarbose, one of such agents, has an effect to prevent or delay diabetes onset when applied to a patient with impaired glucose tolerance (for example, see Reference 10). However, α-glucosidase inhibitors do not affect to increase of blood glucose level by digestion of glucose, monosaccharide (for example, see Reference 11), and an agent to have abroad inhibitory effect of the absorption of carbohydrates have been still desired based on the background of recent changes in constitution of carbohydrates in meals.
In addition, it has been known that blood mannose level increases in diabetes (for example, see Reference 12), and that blood mannose level has a positive correlation with blood glucose level and triglyceride level and a negative correlation with HDL cholesterol in metabolic syndrome (for example, see Reference 13). Mannose and fructose are known to accumulate in renal glomerulus in diabetic rats, and their relations with onset or progression of diabetic nephropathy have been pointed out (for example, see Reference 14). Moreover, it has been reported that mannose and fructose have a protein glycation ability more than 5-times as glucose in glycation reaction with proteins considered as a cause of diabetic complications (for example, see Reference 15). It is known that fructose consumes a lot of ATP through the intracellular metabolic pathway and forms lactose, and that causes a so-called fructose toxicity (for example, see the following Reference 16). Thus, diabetes causes various pathological conditions, and its exacerbation may have a risk to diabetic complications. In recent years, many large-scale clinical studies have been conducted for the prevention of onset or progression of diabetic complications in diabetic treatment, and they have provided many findings (for example, see References 17 and 18). Furthermore, many epidemiologic studies on impaired glucose tolerance and macroangiopathy show that impaired glucose tolerance as the boundary type is also a risk factor in macroangiopathy as well as diabetes. Thus, needs to improve postprandial hyperglycemia have been focused (for example, see Reference 19).
Under the above-mentioned circumstance, as SGLT inhibitors, SGLT1 inhibitors that inhibit the absorption of carbohydrates such as glucose at the small intestine by inhibiting human SGLT1 and inhibit the increase of blood glucose level and are useful specially for improvement of postprandial hyperglycemia and SGLT2 inhibitors, a novel type of antidiabetics, that increase the urinary glucose excretion and lower the blood glucose level by inhibiting excess reabsorption of glucose at the kidney have been found (for example, see References 20 to 28). Since a drug for promoting urinary glucose excretion makes excess glucose excrete into urine and that causes decrease of glucose accumulation in the body, effects to prevent or improve obesity and diuretic effects are expected. In addition, SGLT inhibitors are assumed to be useful for various diseases caused by hyperglycemia and associated with progression of diabetes or obesity. Moreover, as a result of a study using phlorizin known as a SGLT inhibitor, it was confirmed that by inhibiting SGLT urinary glucose excretion increased, blood glucose level lowered and insulin resistance was improved (for example, see References 29 and 30). Thus, in these years, various SGLT inhibitors has been found and are currently under development as treatment agents for diseases associated with glucose, lipid and energy metabolism including diabetes (for example, see References 31, 32 and 33).
In these years, a new gene that codes for a protein having a sodium/glucose cotransporting (hereinafter referred to as SMINT) activity was reported (see Reference 34) as a member of SGLT family. The DNA sequence (see Sequence number 1) and amino-acid sequence (see Sequence number 2) share high sequence homology with SGLT1 and SGLT2 and mammalian cells being expressed these genes show an activity of the sodium-dependent sugar uptake. As mentioned below, SMINT exists highly in human kidney and small intestine and has been confirmed to have a character transporting 1,5-anhydroglucitol, fructose and mannose in addition to glucose, and it has been found that SMINT has a function as 1,5-anhydroglucitol/fructose/mannose transporter. In addition, it was reported that 1,5-anhydroglucitol/fructose/mannose transporter functionally exists in the kidney or the like (for example, see References 35 and 36). Therefore, a SMINT inhibitor is considered to exert an inhibitory effect on 1,5-anhydroglucitol/fructose/mannose transporter and to be useful for the prevention, inhibition of progression or treatment of various diseases caused by excess uptake of glucose, fructose and mannose including diabetic complications such as diabetic nephropathy or the like.
As mentioned above, SGLT inhibitors such as SGLT1 inhibitors, SGLT2 inhibitors, SMINT inhibitors or the like are excellent agents useful for the prevention, inhibition of progression or treatment of various diseases including diabetes and diabetic complications. The present invention provides a novel compound that has an inhibitory effect on SGLT, inhibits the excess uptake of glucose, fructose, mannose and the like (in particular, the absorption in the small intestine or the reabsorption and the uptake into cells in the kidney) and is useful for the prevention, inhibition of progression or treatment of various diseases caused by excess uptake of at least a kind of carbohydrates selected from glucose, fructose and mannose.
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